Natural cellular resistance against bacterial, mycotic, and parasitic infections has generally been attributed to the polymorphonuclear leukocyte (PMN) and the monocytemacrophage system. Natural killer (NK) cells are now emerging as a potential third means of innate resistance against these groups of organisms. Recently we have shown that NK cells are effective in inhibiting the growth of a yeast-like organism, Cryptococcus neoformans, in vitro. The primary objectives of this proposal are to study the effects that NK cells have on C. neoformans in vitro from the standpoints of growth inhibition kinetics and whether the effect of NK cells is fungistatic or fungicidal, to define the potential of NK cells in primary host defense against cryptococci by comparing the effectiveness of NK cells, PMN and macrophages to clear C. neoformans from tissues of mice injected intravenously with the organism, and to determine what effects an intravenous injection of heat-killed C. neoformans will have on the NK, PMN, and macrophage reactivities in a murine model. Unstimulated C57B1/6J bg/bg mutants which have impaired NK activity but apparently normal monocyte functions along with the heterozygote littermates, bg/plus, which are normal in all respects, will be used for the cryptococci clearance experiments. The bg/bg and bg/plus model will be defined with regard to in vitro NK, PMN and macrophage activities against C. neoformans. By purifying populations of these 3 cell types from bg/plus mice and adoptively transferring each separately into cyclophosphamide treated bg/bg mice then challenging with C. neoformans, we hope to demonstrate which cell type affords the animals some protection. The cell type responsible for transfer of resistance will be characterized as to adherence characteristics and surface antigens. The proposed experiments will establish in vitro assays for measuring natural cellular resistance against C. neoformans, will demonstrate the relative roles played by NK cells, PMN, and macrophags in first-line host defense against this organism, and will indicate whether these natural cellular defense mechanisms are altered by C. neoformans. If NK cells prove to be effective in vivo in clearing cryptococci, then this will be a finding of fundamental importance. It will indicate NK cells recognize a broader range of targets than previously considered, and it will define as new primary host defense mechanism against C. neoformans.